DESCRIPTION: (Adapted from the applicant s abstract) During an allograft rejection response, host CD4+ T-cells can recognize donor alloantigens either directly by recognition of mismatched donor MHC class II alloantigens expressed on donor APC, or indirectly by recognition of processed donor alloantigens (MHC or non-MHC) in association with self class II expressed on recipient APC. The role of the direct pathway in allograft reaction is well characterized but little is known about the indirect pathway, despite the fact that it is the physiologic route of antigen recognition and is therefore likely to be a potent element of the antidonor response. This proposal seeks to determine the importance of the indirect pathway in allograft rejection, toward the ultimate goal of developing therapeutic strategies for clinical transplantation that render it ineffective. The fundamental strategy for the proposed experiments is to examine the nature of the immune response when donor grafts that lack class II are placed on normal recipients (i.e., the direct pathway is absent but indirect is intact) compared to that when donor grafts that express class II are placed on recipients that do not (i.e., direct pathway is intact but indirect is absent). These experiments are now feasible due to the recent development of genetically engineered mice that either fail to express class II antigens or express class II only on selected cell types. The proposed studies, using both in vivo and in vitro techniques, will be directed at three specific aims: 1) to determine how T cell responses generated by the indirect pathway compare and contribute to direct responses in cell-mediated rejection of skin grafts; 2) to determine why and how the indirect response is essential for the differentiation of alloantibody forming B-cells; and 3) to explore the failure of direct and indirect stimulation to cause vigorous rejection of primarily vascularized organ transplants.